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Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th edition. New York: W H Freeman; 2002.

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Biochemistry. 5th edition.

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Summary

Glycolysis Is an Energy-Conversion Pathway in Many Organisms

Glycolysis is the set of reactions that converts glucose into pyruvate. The 10 reactions of glycolysis take place in the cytosol. In the first stage, glucose is converted into fructose 1,6-bisphosphate by a phosphorylation, an isomerization, and a second phosphorylation reaction. Two molecules of ATP are consumed per molecule of glucose in these reactions, which are the prelude to the net synthesis of ATP. In the second stage, fructose 1,6-bisphosphate is cleaved by aldolase into dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, which are readily interconvertible. In the third stage, ATP is generated. Glyceraldehyde 3-phosphate is oxidized and phosphorylated to form 1,3-bisphosphoglycerate, an acyl phosphate with a high phosphoryl-transfer potential. This molecule transfers a phosphoryl group to ADP to form ATP and 3-phosphoglycerate. A phosphoryl shift and a dehydration form phosphoenolpyruvate, a second intermediate with a high phosphoryltransfer potential. Another molecule of ATP is generated as phosphoenolpyruvate is converted into pyruvate. There is a net gain of two molecules of ATP in the formation of two molecules of pyruvate from one molecule of glucose.

The electron acceptor in the oxidation of glyceraldehyde 3-phosphate is NAD+, which must be regenerated for glycolysis to continue. In aerobic organisms, the NADH formed in glycolysis transfers its electrons to O2 through the electron-transport chain, which thereby regenerates NAD+. Under anaerobic conditions and in some microorganisms, NAD+ is regenerated by the reduction of pyruvate to lactate. In other microorganisms, NAD+ is regenerated by the reduction of pyruvate to ethanol. These two processes are examples of fermentations.

The Glycolytic Pathway Is Tightly Controlled

The glycolytic pathway has a dual role: it degrades glucose to generate ATP, and it provides building blocks for the synthesis of cellular components. The rate of conversion of glucose into pyruvate is regulated to meet these two major cellular needs. Under physiologic conditions, the reactions of glycolysis are readily reversible except for the ones catalyzed by hexokinase, phosphofructokinase, and pyruvate kinase. Phosphofructokinase, the most important control element in glycolysis, is inhibited by high levels of ATP and citrate, and it is activated by AMP and fructose 2,6-bisphosphate. In the liver, this bisphosphate signals that glucose is abundant. Hence, phosphofructokinase is active when either energy or building blocks are needed. Hexokinase is inhibited by glucose 6-phosphate, which accumulates when phosphofructokinase is inactive. ATP and alanine allosterically inhibit pyruvate kinase, the other control site, and fructose 1,6-bisphosphate activates the enzyme. Consequently, pyruvate kinase is maximally active when the energy charge is low and glycolytic intermediates accumulate.

Glucose Can Be Synthesized from Noncarbohydrate Precursors

Gluconeogenesis is the synthesis of glucose from noncarbohydrate sources, such as lactate, amino acids, and glycerol. Several of the reactions that convert pyruvate into glucose are common to glycolysis. Gluconeogenesis, however, requires four new reactions to bypass the essential irreversibility of three reactions in glycolysis. In two of the new reactions, pyruvate is carboxylated in mitochondria to oxaloacetate, which in turn is decarboxylated and phosphorylated in the cytosol to phosphoenolpyruvate. Two high-energy phosphate bonds are consumed in these reactions, which are catalyzed by pyruvate carboxylase and phosphoenolpyruvate carboxykinase. Pyruvate carboxylase contains a biotin prosthetic group. The other distinctive reactions of gluconeogenesis are the hydrolyses of fructose 1,6-bisphosphate and glucose 6-phosphate, which are catalyzed by specific phosphatases. The major raw materials for gluconeogenesis by the liver are lactate and alanine produced from pyruvate by active skeletal muscle. The formation of lactate during intense muscular activity buys time and shifts part of the metabolic burden from muscle to the liver.

Gluconeogenesis and Glycolysis Are Reciprocally Regulated

Gluconeogenesis and glycolysis are reciprocally regulated so that one pathway is relatively inactive while the other is highly active. Phosphofructokinase and fructose 1,6-bisphosphatase are key control points. Fructose 2,6-bisphosphate, an intracellular signal molecule present at higher levels when glucose is abundant, activates glycolysis and inhibits gluconeogenesis by regulating these enzymes. Pyruvate kinase and pyruvate carboxylase are regulated by other effectors so that both are not maximally active at the same time. Allosteric regulation and reversible phosphorylation, which are rapid, are complemented by transcriptional control, which takes place in hours or days.

Key Terms

glycolysis

lactic acid fermentation

alcoholic fermentation

gluconeogenesis

obligate anaerobe

facultative anaerobe

hexokinase

kinase

phosphofructokinase (PFK)

thioester intermediate

substrate-level phosphorylation

mutase

enol phosphate

pyruvate kinase

bifunctional enzyme

feedforward stimulation

committed step

pyruvate carboxylase

biotin

glucose 6-phosphatase

substrate cycle

Cori cycle

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2002, W. H. Freeman and Company.
Bookshelf ID: NBK22469